DESCRIPTION: (Applicant's Abstract) The development of effective pharmacological treatment strategies for cocaine abuse will depend on a better understanding of the effects of cocaine on brain neurochemistry and CNS function. The aim of this proposal is to use positron emission tomography (PET) imaging techniques in nonhuman primates as an innovative approach to investigate cocaine-induced functional changes in CNS activity. While the neurochemical and behavioral effects of cocaine have been attributed primarily to an interaction with the dopamine system, modulation of serotonin (5HT) activity can reliably alter the behavioral-stimulant and reinforcing effects of cocaine and related psychomotor stimulants. Accordingly, 5HT activity will be manipulated pharmacologically to assess potential changes in sensitivity to the CNS effects of cocaine. Specifically, functional changes in regional cerebral blood flow (rCBF) and dopaminergic activity will be characterized following acute i.v. administration of cocaine in conscious rhesus monkeys. The positron-emitting tracers, 15 0 water and 18F-DOPA will be used to quantify rCBF and dopaminergic activity, respectively. Altered sensitivity to the CNS effects of cocaine will be assessed during acute and chronic administration of the 5HT uptake inhibitor, alaproclate, the 5HT direct agonist, quipazine, and the 5HT2-selective antagonist, ritanserin. The selection of experimental drugs and doses is derived from their pharmacological profile and behavioral pharmacology in nonhuman primates. Additionally, experiments will characterize acute and chronic drug interactions on behavior maintained by i.v. self-administration of cocaine. Concordant results from self-administration and imaging studies will demonstrate a close association between drug-induced functional changes in rCBF and 18F-DOPA uptake and the reinforcing or addictive properties of cocaine. Lastly, PET imaging experiments will characterize longitudinal changes in CNS function and cocaine sensitivity in subjects with a documented history of cocaine exposure. The use of neuroimaging techniques in conjunction with well-established self-administration procedures in nonhuman primates will provide a novel preclinical model to identify pharmacotherapies for cocaine abuse.